Novel 6-keto-4-dehydro-steroids and processes for their manufacture



United States Patent Oflice 3,186,985 Patented June I, 1965 No Drawing. Filed May 7, 1963, Ser. No. 278,743 16 Claims. (Cl. 260-23955) This invention relates to a novel process and to novel products and intermediates produced thereby. More particularly, this invention relates to a novel process whereby a compound of the cyclopentanophenanthrene series having a 3,5a-cyclo-6-kctone system is photolyzed to produce a compound of the cyclopentanophenanthrene series having a A -6-ketone system, which compounds are useful therapeutically and as intermediates in producing other useful compounds. Also included in my invention are novel intermediate some of which are also therapeutically valuable.

My novel process whereby a steroidal 3,5u-cyclo-6-ketone (I) in solution is photolyzed with ultraviolet light to produce a steroidal A -6-ketone (II) may be depicted graphically as shown below (the A and B rings, only, of the steroidal molecule are shown) fl ct;

q in? (I) The following specific reaction is illustrative of my process. A solution of 3,Sa-cycloandrostan-l7 8-ol-6-one 17-acetate in dioxan under a nitrogen atmosphere in a quartz vessel is irradiated for two hours at 25-28 C. with ultraviolet light supplied by a Hanovia 250- watt mercury lamp. Evaporation in vacuo of the irradiated solution followed by purification, such as by crystallization from methanol, yields the A -6-keto steroid, 4-androsten-17,B-ol- 6-one 17-acetate.

By my process, any compound of the cyclopentanophenanthrene series which has a 3,5u-cyclo-6-ketone system may be photolyzed by means of ultraviolet light to give a cyclopentanophenanthrene having a A -6-ketone system. Among the compounds suitable as intermediates in my process are 3,5a-cyclo-6-ketones of the androstane and pregnane series such as those defined by the following structural formula Ia:

(I wherein A is a member selected from the group consisting of hydrogen, (H, (a or B)-lower alkyl), (H, aOH), and methylene; R is a member selected from the group consisting of hydrogen and methyl; X is a member selected from the group consisting of hydrogen and halogen; Y is a member selected from the group consisting of hydrogen, keto, and (H, 50H); and when Y is hydrogen, X is hydrogen; and Z is a member selected from the group consisting of W being a member selected from the group consisting of hydrogen and lower alkanoyl; D being a member selected from the group consisting of hydrogen, lower alkyl, ethinyl, methylethinyl, and halogenoethinyl; V being a member selected from the group consisting of hydrogen, hydroxy, and lower alkanoyloxy; and R being a member selected from the group consisting of hydrogen, hydroxy, and acyloxy; and when V is hydroxy and A is (H, aOH), the 16a,17a-alkylidenedioxy derivatives thereof.

, By lower alkyl is included hydrocarbons having up to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, and tertiary butyl.

Illustrative of the acyl groups which may be present at 21 are inorganic esters such as sulfate and phosphate as Well as acid residues of hydrocarbon carboxylic acids having up to 12 carbon atoms including lower alkanoates such as formate, acetate, propionate, n-butylate, iso-butylate, valerate, iso-valerate, caproate (n-hexanoate);' aromatic acyl residues such as benzoate and toluate, as well as the acyl portions of dibasic acids such as succinate and phthalate.

Some 3,5a-CYClO-6-k6t0 steriod intermediates of my process are known, for example 3,5a-cycloandrostan-l7fiol-6-one l7-acetate and 17a-ethinyl-3,Sawycloandrostan- 17B-ol-6-one. Other 6-keto-3,Sa-cyclo-starting compounds, e.g., 3,5a-cyclopregnane-6,20dione, may be prepared from the corresponding 6-hydroxy-3,Sa-cyclo-steroid, e.g. 3,5u-cyclopregnan-Gfl-ol-ZO-one by oxidation with chromic acid in acetone according to known procedures.

In general, the 6-keto-3,iwcyclo-starting compounds exemplified by Formula Ia may be prepared from a 3-hydroxy-A -steroid by first forming the corresponding A -3- tosylate ester followed by treatment thereof with potassium acetate in acetone/ water according to known procedures whereby is produced the corresponding 3,5ot-CYC10- 6,6-hydroxy intermediary steroids. Conversion to the 3, 5a-cyclo-6-ketone starting compound of our process is then effected by a chromic acid oxidation via known techniques. Thus, for example, l7ot-ethinyl-l9-nor-5-androstene-3,l7}3-diol upon treatment With p-toluenesulfonyl chloride in pyridine is converted to the corresponding 3- tosylate, i.e., 17a-ethinyl-19-nor-5-androstene-3,175-diol3- tosylate, which, in turn, is treated with potassium acetate in acetone/ water according to known techniques to yield l7a-ethyinyl-3,5a-cyclo-l9-nor-androstane 65,175 diol convertible by oxidation with chromic acid to the starting compound, 3,5a-cyclo-l9-nor-androstan-17B-ol-6-one.

In addition to the 6-keto-3,Sa-cyclo-steroid intermediates necessary to my process, as exemplified by compounds defined by Formula la, the corresponding 6,6-hydroxy derivatives as shown below are also valuable intermediates.

ethinyl-19-nor-3,5a-cycloandrostane-6fi,17p die] 17 acetate are valuable as anti-fertility agents.

In my process, prior to irradiation with ultraviolet light, any reactive ketone groups present elsewhere than at -6 in the 6-keto-3,5a-cyclo-starting steroid must be protected, such as by a ketal group, or, in the case of a corticoid, the sensitive side chain at C-17 may be protected by the 17a,20;20,2l bis-methylenedioxy derivative. Such protective groups are preferably introduced prior to formation of the 3,5a-cyclo-6oxygenated system in the preparation of the starting compounds.

In the case of a corticoid starting steroid such as 3,51- cyclopregnane-17a,2l-diol-6,11,20-trione, which is being prepared from the known steroid, -pregnene-3B,17a,2ltriol-1'l,20-dione according to procedures outlined hereinabove, it is usually preferable to introduce the protective grouping, e.g., 17a,20;20,2l-bis-methylenedioxy prior to preparation of the 3-tosylate ester. By Way of example, 5-pregnene-3/3,17a,21-triol-11,20-dione is converted to the corresponding l7a,2'0;20,21-bis-methylenedioxy derivative utlizing known techniques such as with formaldehyde and hydrochloric acid in chloroform. Esterification of the S-hydroxy group with one mole of p-toluenesulfonyl chloride in pyridine followed by treatment of the 3,8-tosyloxy- 5-pregnene with potassium acetate in aqueous acetone yields l7a,20;20,2l-bis-methylenedioxy 3,5 or cyclopregnen-6fl-ol-11-one, convertible by oxidation with chromic acid to the desired starting compound, i.e., 17u,20;20,21- bis-methylenedioxy-3,5ot-cyclopregnane-6,1l-dione. Irradiation of the latter compound in ethanol solution with ultraviolet light yields the novel product, l7a,20;Z0,2l-bismethylenedioxy-4-pregnene-6,1l-dione which is then converted by aqueous formic acid to the novel corticoid analog, 4-pregnene-17a,21-diol-6,11,20-trione.

Similarly, when preparing a 20-keto-2 l-desoxypregnane starting compound, such as 20=ethy1enedioxy-3,5et-cyclopregnane-6,20-dione, the ZO-ketal function is preferably introduced prior to the 3,5ot-cyclo-6-keto system. Thus, 5-pregnen-3fl-ol-20-one is ketalized at C-20 using ethylene glycol according to known procedures. The resulting ZO-ethylenedioxy-S-pregnen-3,8-ol is then converted to the corresponding 3-tosylate ester which, in turn, is treated with potassium acetate in acetone/water to yield 20- ethylenedioxy-3,5a-cyclopregnan-6,5-ol convertible by oxidation with chromic acid to the desired starting compound, 20-ethylenedioxy-3,5a-cyclopregnan-6-one.

When a 16ot-hydroxy-3,5a-cyclo-6-keto-A -steroid is desired, the 160t-hydlOXY group is preferably introduced into the molecule after oxidation of the 6,8-hydroxy function in a 3,5ot-cyclo-intermediate of Formula III to the corresponding 6-keto-3,5ot-cyclo-intermediate of Formula In. This is effected conveniently via known microbiological techniques such as that utilizing the microorganism Streptomyces roseochromogenus (Waksman Collection No. 3689).

Thus, when it is desired to prepare 4-pregnene-l6a,17a, 2l-triol-6,20-dione, the l6a-hydroxy function may be introduced by the action of Streptomyces roseochromm genus into the 6-keto intermediate, l7ot,20;20,21-bis methylenedioxy-3,5a-cyclopregnane-6,ll-done prior to irradiation with ultraviolet light. The resulting 170;,20; 20,21-bis-methylenedioxy 4 pregnene-16or-ol-6,l1-dione is then converted by aqueous formic acid to the novel corticoid analog, 4 pregnene-loa,17a,21-triol-6,11,20- trione. Alternatively, the lfia-hydroxy function may be introduced into the corresponding l6-desoXy-M-6-keto steroid, 4-pregnene-17a,2l-diol-6,1 1,20-trione.

In general, in addition to having ketone groups other than at C-6 protected by a derivative such as a ketal, and the corticoid C-l7 side chain protected by a derivative such as the 17u,20;20,2l-bis-methylenedioxy group, the 6-keto-3,5ot-cyclo-starting steroids of my process are preferably devoid of other reactive chromophores in the molecule having an ultraviolet absorption in the 220-400 m region, such as conjugated dienes, 06"dlkfi" tones, (X-OXlIIl-lnO ketones, nitrite esters, etc.

Radiant energy containing ultraviolet light in the range of 2000-4400 A. for use in my process is conveniently supplied by a Hanovia high pressure mercury arc lamp with a mercury sleeve, while the 3,5ot-cyclo-6-keto steroid to be irradiated is contained in an ultraviolet transmitting vessel such as a quartz, vessel or a water-cooled Vycorimmersion Well.

During the course of the photolysis of a 3,5a-cyclo- 6-keto steroid, a stream of nitrogen or other. inert gas is generally bubbled through the solution (although this is not always necessary).

Solvents suitable for use in my process are nonreactive solvents, which are transparent to ultraviolet radiation and in which the 3,5a-cyclo-6 -keto starting steroid is soluble. Exemplary of solvents which may be used are ethers (e.g., dioxan, tetrahydrofuran), alcohols (e.g., methanol, ethanol), and aliphatic hydrocarbons (e.g., heptane, hexane, etc.). The preferred solvents are dioxan and ethanol.

The temperature at which the photolytic process of this application is carried out is within the range of 40 C. to +40 C. depending on the freezing or boiling points of the solvent used.

Typical 6-keto-A -steroids which may be prepared by my process via the ultraviolet irradiation of the corresponding 6-keto-3,5arcyclo-steroids are exemplified by compounds of the following Formula Ila:

rep A (Ila) wherein A, R, X, and Z are as defined for Formula Ia and Y is a member selected from the group consisting of hydrogen and keto, and when Y is hydrogen, X is hydrogen.

The 6-keto-A -steroid's of Formula Ila are therapeutically valuable and, in general, posses therapeutic prop.- erties similar to those possessed by the corresponding 3-keto-A -steroids and may be administered in similar pharmaceutical forms and for the same indications for which the corresponding 3-keto-A -steroids would be applicable. 6-one possesses progestational activity similar to that of ethisterone (l7a-ethinyl-4-androsten-17fi-0l-3-one) and may be administered orally in the form of tablets or capsules. The pharmaceutical preparations are prepared according to procedures well known in the art.

The novel 6-keto-A -steroids of Formula IIa having a cortical side chain at C-17, i .e., those compounds wherein Z is d on V being hydrogen, hydroxy, and lower alkanoyloxy, are progestational agents and, thus, are useful in the treatment of ailments such as habitual and threatened abortion, premature labor, premenstrual tension, female hypogonadism and the like.

For example, 17a-ethinyl-4-androsten-17,8-01- The 6keto-A -steroids prepared by my process wherein Z is W and D being defined as for Formula Ia, possess anabolic and androgenic activity and may be used in a manner similar to known anabolic/ androgenic agents in the treatment of ailments such as geriatric disorders, metabolic imbalance in children, and post-surgical therapy. Additionally, 17a-allrinyl derivatives of Formula Ha, such as 17a-ethinyl-l9-nor-4-androsten-17B-ol-6-one, possess progestational and anti-fertility properties. The preferred class of compounds of my invention are the 17usubstituted-6-keto-l7o-hydroxy-A -androstenes of formula Ila including the novel intermediates useful in their preparation In addition to being therapeutically active per se, the 6-ket0-A -steroids of this invention are valuable as intermediates in preparing a novel class of therapeutically valuable steroids, i.e., 3-desoxy-4,6-dienes such as shown below in Formula IV wherein A, R, X, Y, and Z are as defined for Formula Ia.

and

Thus, reduction of a G-keto-M-steroid of Formula Ila, e.g., l'la-ethinyl-l9-nor-4-androsten-17B-ol-6-one 1'7-acetate, with sodium borohydride or lithium aluminum hydride followed by acid treatment of the resulting M-G-hydroxy steroid, e.g., l7oc-ethinyl l9-nor-4-androstene-6;3,l7B-diol l7-acetate, or, alternatively, by dehydration of the 6-tosylate or 6-mesylate thereof with an agent such as collidine will yield a 3-desoxy-4,6-diene; e.g., 17aethinyl-19-nor-4,6-androstadiene-175-01 l7-acetate, valuable as an anti-fertility agent. In general, the novel 3- desoxy-4,6-dienes of Formula 1V possess a utility similar to that of their 3-desoxy-6-keto-4-monoene precursors of Formula Ho.

The following are examples which illustrate our invention. It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown or described as obvious modifications and equivalents will be apparent to one skilled in the art. The invention is, therefore, to be limited only by the scope of the appended claims.

EXAMPLE 1 4-andr0sten-17fl-0l-6-0ne l 7-acemte Irradiate a solution of 3,Sa-cycloandrostan-6-one-l7B- ol 17-acetate (4.0 g.) in dioxan (150 ml.) at 25-28 C. under an atmosphere of nitrogen in a quartz vessel using a Hanovia 250-watt mercury lamp. After 2 hours of irradiation, evaporate the solution in vacuo to a residue. Purify the residue by crystallization twice from methanol, then twice from isopropyl ether, to give 4-androsten-l76- ol-6-one 17,8-acetate, MP. 159464" C., [@1 +26.

Chromatography of the mother liquors on Florisil gives, on elution with hexane: benzene mixtures, more of 4- androsten-l7,8-ol-6-one 17B-acetate.

Irradiate a solution of l7a-ethinyl3,5a-cycloandrostan- 17,8-01-6-0ne (3 g.) in ethanol (150 ml.) in the manner of Example 1 to give l7a-ethinyl-4-androsten-l75-01- 6-one.

6 EXAMPLE 3 1 7a-ethinyl-3 ,5 ot-cycloestran-l 7 fi-ol-6-0ne A. 17a-ETHINYL-5-ESTRENE3B,17B-DIOL 3-p-TOLUENESULPHONATE To a solution of l7ot-ethinyl-5-estrene-3B,17fi-diol (10 g.) in pyridine (50 ml.) at 05 C., add p-toluenesulphony] chloride (15 g.) and allow the mixture to stand at (l 5 C. for 20 hours. Then dilute the reaction mixture with water and filter the resultant precipitate. Wash the residue on the filter with water and dry to give 170:: ethinyl-S-estrene-Pa/S,l7/3-diol 3-p-toluenesulphonate.

Reflux for minutes a solution of l7a-ethinyl-5-estrene-3B,l7{3-diol 3-p-toluenesulphonate (10 g.) in acetone (175 ml.) and water (175 ml.) containing potassium acetate (14 g.). Cool the solution, then dilute with water and extract with ether. Combine the ethereal extracts and wash with water, dry (Na SO and evaporate to a residue substantially of 17a-ethinyl-3,5a-cycloestrane-6fi, l'ifi-diol. Purify by crystallization from acetone-hexane.

C. 17a-ETHINYL-3,5a-CYCLOESTRAN-I'ZB-OL-B-ONE To a solution of l7a-ethinyl-3,5a-cycloestrane-6fl,17,8- diol (2 g.) in acetone (200 ml.) at 0-5 C. add dropwise chromic acid-sulphuric acid reagent (8 N with respect to oxygen; 3.0 ml.) and then store the mixture overnight at 5 C. Pour the reaction mixture into water, filter the resultant precipitate, then wash with Water and dry. Purify by crystallization from acetone-hexane to give l7a-ethiny-l- 3 ,5 u-cycloestranl7fi-ol-6-one.

EXAMPLE 4 1 7 a-ethinyl-4-estren-1 7,8-0l-6-0ne Irradiate a solution of 17a-ethinyl-3,Sa-cycloestran- 17flo1-6-one (4 g.) in dioxan (120 ml.) in the manner of Example 1. Isolate and purify the resultant product in the described manner to give 17a-ethinyl-4-estren-17f3-ol- 6-one.

EXAMPLE 5 17,20:20,21-bismethylenedioxy derivative of S-pregnene- 3 8,1 7a,21-tri0I-11,20-di0ne- A. 5-PREGNENE-3fl,17a,21-TRIOL-11,20-DIONE Stir at room temperature for 18 hours a solution of 5- pregnene-3,6,l7u,21triol-11,20-dione 21-acetate (1.0 g.) in methanolic perchloric acid (40 ml.; prepared from 39.0 ml. of methanol and 1.0 ml. of 70% perchloric acid). Then dilute the solution with water and filter. Wash the residue on the filter with water and dry to give S- regnene- 3l3,17oc,21-t1iOl-11,20-di01'1e.

B. 17,20 20,21-BISMETHYLENEDIOXY DERIVATIVE 013 5-PREGNENE-3fl,17a,21-TRIOL-1'1,20 DIONE Prepare a solution of 5.0 g. of 5-pregnene-3l3,17a,21- triol-l1,20-dione (Part A of this example) in chloroform (200 ml), 37% aqueous formaldehyde (50 ml), concentrated hydrochloric acid (50 ml.) and stir the solution vigorously at room temperature for 48 hours. Add water to the reaction mixture and separate the layers. Dilute the lower layer with chloroform, and wash with 10% aqueous potassium hydroxide, then with water. Dry the solution (Na SO and evaporate to a residue. Purify the residue by crystallization from acetone-hexane to give 17,20:20,21-bismethylenedioxy derivative of 5-pregnene- 35,17cc,2l-t1l0l-11,20-di0116.

EXAMPLE 6 17,20 :20,21-bz'smethylenedioxy derivative of 5 -pregnne- 36,115,] 7oz,21tetrol-20-0ne To a stirred solution of 2 g. of the 17,20:20,2l-bismethylenedioxy derivative of 5-pregnene-3f3,l7a,2l-triol-l1, 20-dione in tetrahydrofuran ml.) at 0-5 C. add lithium aluminum hydride (1.0 g.) in ether (100 ml.) and stir the mixture at 05 C. for one hour. Destroy the excess hydride by dropwise addition of ethyl acetate, and

amass? then add a saturated aqueous solution of sodium sulphate until the precipitated aluminum salts begin to coagulate. Add solid sodium sulphate, decant the supernatant liquid and evaporate to a residue substantially of 17,20:20,21- bismethylenedioxy derivative of 5-pregnene-3fi,11fi,17a, 21-tetrol-20-one.

EXAMPLE 7 17,20120,21-bismethylenedioxy derivative of 3,5u-cycl- A. 17,20:20,21-BISMETHYLENEDIOXY DERIVATIVE OF -PREGNENE 3fi,11fl,17a,21 TETROL--ONE 3,8-TOS- YLATE To a solution of the 17,20:20,21-bismethylenedioxy derivative of 5-pregnene-3/3,1lfl,17u,21-tetrol-20-one (5 g.) in pyridine ml.) at 05 C. add p-toluenesulphonyl chloride (7.0 g.) and allow the reaction mixture to stand at 5 C. for 20 hours. Dilute the reaction mixture with water and filter the resultant precipitate. Wash the residue on the filter with Water and dry to give 17,

20:20,21-bismethylenedioxy derivative of 5-pregnene-3B,

B. 17,20:20,21-BISMETHYLENEDIOXY DERIVATIVE OF 3,5a-CYCLOPREGNANE-GB,11B,17a,21-TETROL-20-ONE Reflux for 90 minutes a solution of the Bfl-tosylate prepared in Example 7A (1.0 g.) in acetone (20 ml.) and Water (20 ml.) containing potassium acetate (1.4 g.).

Isolate the resultant product in the manner of Example 3B to give 17,20:20,21-bismethylenedioxy derivative of 3 ,5 a-cyclopregnane-6B, 1 1,8, l7a,2 l-tetrol-20-one.

C. 17,20:20,21-BISMETHYLENEDIOXY DERIVATIVE 0F 3,5a-CYCLOPREGNANE-l1B,l7a,21-TRIOL6,20-DIONE To a solution of the 3,5a-cyclopregnane prepared as in Example 7B (4.06 g.) in acetone (400 ml.) at 05 C.,

add chromic acid-sulphuric acid reagent (8 N with respect to oxygen; 0.25 ml.) and keep the solution at 0-5" C. for

18 hours. Isolate and purify the resultant product in the manner of Example BC to give 17,20:20,21-bisrnethylenedioxy derivative of 3,5a-cyclopregnane-11fl,17a,21- triol-6,20-dione.

EXAMPLE 8 17,20:20,2I-bismethylenedioxy derivative of 4-pregnene- 11,8,17a,21-tri0l-6,20-di0ne Irradiate an ethanolic solution of the 17,20:20,21-bismethylenedioxy derivative of 3,5a-cyclopregnane-l113,17a, 21-triol-6,20-dione in the manner of Example 1 and isolate and purify the resultant product in the described manner to give 17,20:20,21-bismethylenedioxy derivative of 4-pregnene-11,8,17a,21-trio1-6,20-dione.

EXAMPLE 9 4-pregnene-1 15,1 7a,21-tri0l-6,20-di0ne 21 acetate Reflux a solution of the 17,20:20,21-bismethylenedioxy derivative of 4-pregnene-11B,17a,21triol 6,20-dione (100 mg.) in 60% aqueous acetic acid (10 ml.) for 1 hour, and then dilute the mixture With water and filter, Wash, and dry the resultant precipitate. Acetylate the dried precipitate with pyridine-acetic anhydride (10 ml. pyridine and 1 ml. acetic anhydride per gram of precipitate) at room temperature for 18 hours, and crystallize the resultant product from acetone-hexane to give 4-pregnene-l1,8,17u,21-triol-6,20-dione 2l-acetate.

EXAMPLE 10 1 7a-ethinyl-3,5a-cyclo-I9-n0r-andr0stane- 6B,] 75-di0l 17-acetate' A. 17a-ETHINYL IQ-NOR-ELANDROSTENE-bBJZfi-DIOL 3-TOSYLATE 17-ACETATE To a solution of 17a-ethinyl-19-nor-5-androstene-3fl, 17,8-diol 17-acetate (1 g.) in pyridine (5 ml.) add p-toluenesulfonyl chloride (1.5 g.), at 0 C. Keep the solution at 0 C. for minutes, and then store at 5 C. for 18 hours. Pour the reaction mixture into water and ice, and filter 011 the precipitated solid, wash with water, and dry in vacuo at room temperature to a residue comprising 17a-ethinyl-19-nor-5 androstene-3fi,17B-diol 3-tosylate 17- acetate. i

B. 17a-ETHINYL-3,5a-CYCLO-lQNOR-ANDROSTANE- GB,17B-DIOL 17-ACETATE Dissolve the 3-tosylate (950 mg.) (prepared as in part A of this example) in acetone (20 ml.) and add a solution of potassium acetate (1.6 g.) in water (20 ml.). Reflux the mixture for 1 /2 hours, then cool and pour into water and ice. Filter the resultant suspension and wash the residue on the filter with water, dry, and subject to partition chromatography on a column of Chromosorb W, using the ligroin-propylene glycol system. After some initial oily fractions, a series of crystalline fractions is collected. Combine these crystalline fractions and crystallize from ether-hexane to give 17ot-ethinyl-3,5a-cyclo- 19-nor-androstane-6p,17,8-diol 17-acetate, M.P. 154-156 C., [@1 30 (CHCl EXAMPLE 1 1 To a solution of 17a-ethinyl-3,5a-cyclo-l9-nor-androstane-6,8,17fi-diol 17-acetate (330 mg.) in acetone (20 ml.) at 05 C., add a solution of chromium-trioxide in sulfuric acid (Jones reagent) until a permanent orange color results. Leave the mixture at room temperature for 30 minutes, then add water. Filter off the resulting solid, Wash with water, dry, and subject to partition chromatography on Chromosorb W, using the ligroin-propylene glycol system. Combine the crystalline fractions and crystallize from ether-hexane, to give 17a-ethinyl-3,5acyclo 19 nor androstan 17,8 ol 6 one 17 acetate, M.P. 163 C., [uJ 57.

EXAMPLE 12 1 7 a-ethinyl-I 9-n0r-4-androsten-1 7,6-0l-6-0ne 1 7 -acetate Irradiate a solution of 17a-ethinyl-3,5ot-cyclo-19-norandrostan-l7B-ol-6-one 17-acetate (1.0 g.) in dioxan (150 ml.) in a quartz cell, at 26 C. with a 200 watt Hanovia mercury lamp for two hours, under nitrogen. Evaporate the solution to dryness in vacuo, and chromatograph the resultant residue on Florisil eluting Withether-hexane mixtures to give 17ot-ethinyl-l9-nor-4-androsten-175-01-6- one 17-acetate, M.P. 208-215" C., [cd 60.

EXAMPLE 13 l 7a-chl0r0ethinyl-19-n0r-5-andr0stene-35J 7,8-di0l A. 17 a.CHLOROETHINYL-19-NOR-3,5-ANDRO- STADIENE-3,17B-DIOL DIACETATE Dissolve 14.2 g. of 17e-chloroethinyl-19-nor-4-androsten-17fl-ol-3-one in 142 ml. of acetic anhydride to which has been added 1.42 g. of p-toluenesulfonic acid. Heat the solution on a steam bath for one hour; then cool and pour into ice water. Neutralize the reaction mixture with 10% aqueous potassium bicarbonate. Filter the resultant precipitate of l7a-chloroethinyl-19-nor3,5-androstadiene- 3,17B-diol diacetate, wash with Water, and dry. Purify by crystallization from methanol. 7

B. lTwCHLOROETHINYL-lQ-NOR-E-ANDRO- STENE-3B,17fi-DIOL 17-ACETATE Dissolve 7 g. of 17occhloroethinyl-19-nor-3,5-androstadiene-3,17fl-diol diacetate in 250 ml. of dimethyl formamide and add 4.13 g. of sodium borohydride in 63 ml. of Water. Heat the reaction mixture on a steam bath for 10 minutes, cool and pour into Water. Bring the reaction mixture to neutrality with glacial acetic acid. Filter the resultant precipitate of substantially 17m-chloroethinyl-19-nor-5-androstene-3B,17B-diol 17-acetate. Wash with Water and dry. Purify by crystallization from methanol.

C. 17a-CHLOROETHINYL-lQ-NOR-5-ANDRO- sTENE-3B,175-DIOL In a manner similar to that described in' Example 6, treat a chloroethinyl 19 nor 5 androstene 3,8,

17B-diol l7-acetate in tetrahydroturan with lithium aluminum hydride in ether. Isolate the resultant product in the described manner to obtain l7a-chloroethinyi-l9 nor-S-androstene-Sfi,l7B-diol.

In a manner similar to that described in above procedures A, B, and C, l7m-chloroethinyll-androsten-17B-ol- 3-one is reacted with p-toluenesultonic acid in acetic anhydride to obtain l7a-chloroethinyl-3,S-androstadiene- 3,175-diol diacetate which, in turn, is reacted with sodium borohydride in dimethyl formamide to give Not-chloroethinyl-S-androstene-3B,17/3-diol 17-acetate, which is then reduced with lithium aluminum hydride in tetrahydrofuran to give 17a-chloroethinyl-5-androstene-3,8,17B-diol.

EXAMPLE 14 1 7a-chl0r0ethinyl-Z 9-n0r-4-androsterz-l 7fl-0l-6-0rze 17-acetaze A. 17:1.CHLOROETHINYL-19-NOR-5-ANDROSTENE-3B,l7 18- DIOL 3-p-TOLUENESULFONATE PLACE-TATE In a manner similar to that described in Example 3A, treat l7tz-chloroethinyl 19 nor-5-androstene-3 6,17B-diol l7-acetate in pyridine with p-toluenesulfonyl chloride. The resultant product is isolated in the manner described to give 17u-chloroethinyl-19-nor-S-androstene-3,6,17fi-diol 3-p-toluenesulfonate 17-acetate.

Similarly, 17a-chloroethinyl 5 androstene-3,6,l7fi-diol l7-acetate, l7a-chloroethinyl-l9-nor-5-androstene-35,175- diol, l7a-chloroethinyl 5 androstene-3[3,l75-diol, 170cmethyl-19-nor-5-androstene-3/3,17B-diol, and 17Ct-I'I16III1Y1- 5-androstene-3 [3,17fl-diol are each reacted with p-toluenesulfonyl chloride in pyridine to obtain the respective 3-ptoluenesulfonate esters, i.e., 17m-chloroethinyl-5-andro stene-3fi,l7fi-diol 3-p-toluenesulfonate 17-acetate, 17achloroethinyl 19 nor-5-androstene-3[3,17,8-diol 3-p-toluenesulfonate, 170a chroethinyl-S-androstene-3 {3,17 fl-diol 3-p-toluenesulfonate, li'a-methyl-l9-nor-5-androstene-3fl, 17fi-diol 3-p-toluenesulfonate, and 17a-methyl-5-androstem-3,6,1'lQ-diol-B-p-toluenesulfonate.

B. 17a-CHLOROETHINYL-19 NOR3,5a-CYCLOANDRO- STANE-6B,17B-DIOL u-acnrscrn In a manner similar to that described in Example 313, treat 17a-ch1oroethinyl 19 nor-5-androstene-3 13,17 ,B-diol S-p-toluenesultonate l7-acetate with potassium acetate in acetone. Isolate the resultant product in the described manner to give l7a-chloroethinyl-19-nor-3,5 x-cycloandrostane-6B,l75-diol 17-acetate.

In a similar manner treat each of 17 a-chloroethinyl-fiandrostene-3fi,17fi-diol 3-p-toluenesultonate 17-acetate, 17Lx-chloroethinyl l9 nor-5-androstene-3B,17B-diol 3-ptoluenesulfonate, 170t-ChlOIOfithlIlYl-5-2lIldl'0St6l'l6-3fi,17fi diol 3-p-toluenesulfonate, Her-methyl-l9-nor-5-androstene-3{3,17B-diol 3-p-toluenesu1fonate, and 17a-methyl-5- androstene-35,l7fi-diol 3-p-toluenesulfonate with potassium acetate in acetone to obtain, respectively, 17 oc-ClllOIO- ethinyl-3,Su-cyclOandrostane-6BA7,6-diol 17-acetate, 17achloroethinyl l9 nor-3,5oc-cycloandrostane-6fi,17,6-diol, 17a-chloroethinyl-3,5u-cycloandrostane-6,6,17,8-diol, 17amethyl-19-nor-3,Su-cycloandrQstane-QG,l7l3-diol, and 17amethyl-3,5u-cycloandrostane-65,17,8-dio1.

C. l7a-CHLOROETHINYL-19NOR-3,5a-CYCLOANDRO- STANJ'm-OL-GONE 17-ACETATE In a manner similar to that described in Example 3C, treat 17a-chloroethinyl 19-nor-3,Sa-cycloandrostane-Gfi, 17fl-diol 17-acetate in acetone with chromic acid in sulfuric acid reagent. Isolate the resultant product in the described manner to give l7m-chl0roethinyl-l9-nor-3,Smcycloandrostan-l7fl-ol-6-one 17-acetate.

Similarly, 17oz chloroethinyl-3,Sa-cycIQandrostane-Se, I'IB-diol l7-acetate, 17u-chloroethinyl-l9-nor-3,Sa-cycloandrostane-6fi,17B-diol, 17a chloroethinyl-B,5a-cycloandrostane-6[3,l7;8-diol, Nix-methyl-19nor-3,5a-cycloandrostane-6t8,l7B-diol, and 17ot-methyl-3,Sa-cycloandrostane- 6,8,l7B-diol are each reacted with chromic acid/sulfuric acid reagent to give, respectively, l7a-chloroethinyl-3,5ot-

Id cycloandrostan-l7B-ol-6-one l7-acetate, l7e-chlcroethinyll9-nor-3 ,5 rz-cycloandrostam17,6-ol-6-one, 17cc chloroethiuyl-3,5a-cycloandrostan 17;? ol 6-one, 17a-methyl-l9- nor-3,5ct-cycloandrostan-175-01-6-one and 17a-methyl-3, fiu-cycloandrostan-l7fi-ol-6-one.

D. 17u-CHLOBOETHINYIrl9-NOR-4-ANDROSTEN- 17 B-OL6-ONE l'i-ACETATE In a manner similar to that described in Example 1, irradiate a dioxane solution of 17a-chloroethinyl-l9-nor- 3,5ot-cycloandrostan-17fl-ol-6-one l7-acetate with a 250 watt mercury lamp. Isolate the resultant product in the described manner to give 17a-chloroethinyld9-nor-4-an drosten-17fl-ol-6-one 17-acetate.

Similarly, dioxan solutions of l7u-chloroethinyl-3,5ucycloandrostan-l7B-ol-6one 17-acetate, 17a-chloroethinyl-l9-nor-3,5ot-cycloandrostan-17/3-0l-6-one, l7a-chloroethinyl-3,fiot-cycloandrostan-17,8-01-6-0ne, 17oc-l'116thYl-l9- nor-3,5a-cycloandrostan-l7fl-ol-6-one and 17a-methyl-3, 5a-cycloandrostan-l75-ol-6-one are each irradiated with ultraviolet light to give, respectively, 17a-chloroethinyl- 4-androsten-l7f3-ol-6-one l'7-acetate, l'lot-chloroethinyl- 19-nor-4-androsten-l7B-ol-6-one, l7a-chloroethinyl-4-androsten- 17 B-ol-G-one, lt-I'Il6thYl-19-I1Gf-4-al1dl'OSIBII-17f9- ol-6-one, and l7e-methyl-4-androsten-l7 8-ol-6-one.

EXAMPLE 15 4-pregnene-6,20-dione A. 20-ETHYLENEDIOXY5PREGNEN-3,B-OL

Dissolve 1 g. of 5-pregnen-3fi-ol-20-one in ml. of benzene and add 7.5 ml. of ethylene glycol together with 50 mg. of p-toluenesulfonic acid. Heat the reaction mixture at reflux with a Water separator for 20 hours. Cool the reaction mixture and add about 10 ml. of saturated sodium bicarbonate solution. Extract the reaction mixture with ether, Wash the combined extracts with Water, dry over sodium sulfate, and evaporate to a residue comprising 20-ethylenedioxy-5-pregnen-3fi-ol.

B. 20-ETHYLENEDIOXY5QPBEGNEN-EB-OL 3-p-TOLUENESULFONATE In a manner similar to that described in Example 3A, treat ZO-ethylenedioxy-S-pregnen-3B-ol with p-toluenesulfonyl chloride in pyridine. Isolate the resultant product in the described manner to give ZO-ethylenedioxy-S- pregnen-S [3-01 3-p-toluenesulfonate.

C. 20-ETHYLENEDIOXY-3,5a-CYCLOPREGNAN6B-OL In a manner similar to that described in Example 3/3, treat ZO-ethylenedioxy-S-pregnen-BB-ol 'S-p-toluenesulfomate with potassium acetate in aqueous acetone. Isolate and purify the resultant product in the described manner to give 20-ethylenedioxy-3,Su-Cyclopregnah-Gfi-Ol.

D. 20ETHYLENEDIOXY-3,5a-CYCLOPREGNAN-6-ONE In a manner similar to that described in Example 3C, treat 20-ethylenedioxy-3,Sawyclopregnan-(Sfibl with chromic acid in sulfuric acid reagent. Isolate the resultant product and purity in the described manner to give 20- ethylenedioxy-3,5 x-cyclopregnan-ti-one.

E. 20-ETHYLENEDIOXY-4-PREGNEN-s-ONE In a manner similar to that described in Example 1, irradiate a solution of 20-ethylenedioxy-3,Sa-cyclopregnan-6-one in dioxan with a 250 watt mercury lamp. Isolate and purify the resultant product in the described manner to give ZO-ethylenedioxy-4-pregnen-6-one.

F. 4-PREGNENE-6,20DIONE Reflux a solution of mg. of ZO-ethylenediox -4-pregnen-G-one in 10 ml. of 60% aqueous acetic acid for one hour. Dilute the mixture with water, and filter, Wash and dry the resultant precipitate comprising 4-pregnene- 6,20-dione. Purify by crystallization from acetone-hexane.

In a similar manner, by going through a sequence of reactions similar to those described in Examples 15A through 15F, 16wmethyl-S-pregnene-3B-ol-20-one, 1613- 1 1 methyl-fi-pregnene-3 8-ol-20-one, 5-pregne1re-38,17ot-diolone, 168-methyl-5-pregnene-38,17a-diol-20 one, and 16a-methyl-5-pregnene-38,17a-diol-20-one are each reacted with ethylene glycol in the presence of p-toluenesulfonic acid to obtain the corresponding respective ZO-ethylene ketal derivatives, each of Which are then reacted with p-toluenesulfonyl chloride in pyridine to obtain, respectively, 16a-methyl-20-ethylenedioxy-5-pregnene-38-ol 3-ptoluenesulfonate, 168 methyl ZO-ethylenedioxy-S-pregnene-3 8-01 3-p-toluenesulfonate, ZO-ethylenedioxy-S-preg- V nene-38,17ot diol 3-p-toluenesulfonate, l68-methyl-20-ethylenedioxy 5-pregnene-38,17o-diol 3-p-to1uenesu1fonate,

and 16a-methyI-ZO-ethylenedioxy-5-pregnene-3 8,1Z'ot-diol respectively, 160: methyl-2O-ethylenedioxy-4-pregnene-6- one, 168-rnethyl-20-ethylenedioxy-4-pregnene-6-one, 20- 'ethylenedioxy 4-pregnene-17u-ol-6-one, 168-methyl-20- ethylenedioxy-4-pregnene-17a-ol-6-one and l6oc-methyl- 20-ethylenedioxy-4-pregnene-17u-ol-6-one. Hydrolysis of each of the ZO-ethylene ketal derivatives is effected by means of 60% aqueous acetic acid in the manner described in Example 15F to obtain, respectively, 16ot-methyl-4-pregnene 6,20-dione, 168-methyl-4-pregnene-6,20-dione, 4- pregnene-17a-ol-6,20-dione, 168-methyl-4-pregnene-17aol-6,20-dione and 16a-rnethy1-4-pregnene-17a-.o1-6,20-dione.

EXAMPLE 16 J 7ot-ethinyl-3,5ot-cycloandr0stan-1 78-0l-6,I1-di0nes A. 17a-ETHINYL-3,5-ANDROSTADIENET3J18,178- TRIOL TRIACE'IATE ESTERS In a manner similar to that described in Example 13A, treat 9lx-fiuOl'O-170t-Btl'lll'l'f/I-4-3I1CII'OSIEI16-1 18,178-diol-3- one With acetic anhydride in p-toluenesulfonic acid. Isolate and purify the resultant product in the described manner to give 9ot-fiuoro-17tx-ethinyl-3,S-androstadiene- 3,1'18,178-triol triacetate.

In a similar manner, each of 9u-fiuoro-1Ga-methyI- I7u-propinyl-4-androstene-118,178-

diol-3-one are reacted with acetic anhydride and p-toluenesulfonic acid in the above-described manner to give, respectively, 16ot-methyl-17ot-ethiny1-3 ,5 -androstadiene-3 ,l18,178-

triol triacetate, 168-methyl-17 x-ethinyl-3,5-androstadiene-3,l 18,'178-triol triacetate,

nets to give 12 9ot-fluoro l6a-methyl-17ot-ethinyl-3,5 androstadiene- 3,118,178-triol triacetate, 9ot-iluoro-l6a-ethyl-17ot-ethinyl-3,S-androstadiene- 3,1 18,178-trio1 triacetate, 9cxflu'cro-l 68-ethyll7ix-ethinyl-3,5-androstadiene 3,118,178-trio1triacetate, Y 1a-methyll7ot-propinyl-3,5-and1ostadiene-3,178-diol- 1 Lone diacetate, 168-methyl-17a-propinyl-3,'5-androstadiene-3 ,178-diol- '1 l-one diac etate, and a 9ct-fiuoro-l6zx-methyl-17ix-propinyl-3,S-androstadiene- 3,118,178-tri0l triacetate.

B. 17a-EIHINYL-5-ANDROSTENE-38,118,178-TRIOL 11,17-DIACETATE ESTERS In a manner similar to that described in Example 13B, treat each of the 17a-ethinyl-3,S-androstadienes prepared in the preceding example with sodium borohydride in dimethylformamide. Isolate and purify the resultant prod- 9a-fluoro-17a-ethinyl-5-androstene-38,11,8,178-triol 11,17-diacetate,

16a-methyl-i-androstene-38,1l8,'178-triol 1 1,17-diacetate,

9ec-fluoro-16ix-methyl 17ot-ethinyl5-androstene-3 8, 1 18,

17,8-triol 11,-17-diacetate,

9a-fluoro-1 6a-ethyl-17a-ethinyl-S-androstene-38,1 18, 178- triol l 1,17-diacetate, 9ot-fluoro-168-ethy1-17ot-ethinyl-5-androstene-38;118,178-

triol 11,17-diacetate,

v 16a,-methyl-17a-propinyl-5-androstene-38,178-diol-1'1- one 17-acetate, l68-methyl-17a-propinyl-5-androstene-38, 178-diol-l lone 17-acetate, and 9u-flu0ro-16a-rnethyl-17apropinyl-S-androstene-38, 1 18,

178-tri0l 1'1,17-diacetate, respectively.

C. 17a-ETHINYL-5-ANDROS'1ENE-38,118,178-TRIOLS In a manner similar to that described in Example 13C, treat each of the 17a-ethinyl-5-androstenes prepared in Example 16B With lithium aluminum hydride in ether. Isolate the resultant products in the described manner to give 9a-fiuoro-l7a-ethinyl-5-androstene-38,1 18,178-trio1, l6uc-II16thYl-17ot-6thiI1Yl-5-Eil1d108t6l'l6-3,3,1 18, 178-triol, 168-methyl-17a-ethinyl-5-androstene-38,l 18,178-triol, 9ot-fluoro-l6u-methyl-17a-ethinyl-5-androstene-38,1 18,

178-triol, I 9a-fiuoro-16a-ethyl-17ot-ethinyl-5-androstene-38, 1 18,178-

triol, 9e4-flllO1O-l 68-ethyl l7ot-ethinyl-5-androstene-38, 1 18,178-

triol V 1ct-inethyl-17ot-propinyl-5-androst'ene-38,1 18,178-triol, i 168-methyl-17a-propinyl-S-androstene-38,1 18,178-triol,

and 9u-fiuoro-16a-methyl-l7a-propinyl-5-androstene- 38,1 18,178-triol,respectively.

D. 17a-ETHINYL-5-ANDROSTENE-3B,118,17B-TRIOL 3-p-TOLUENESULFONATE ESTERS In a manner similar to that described in Example 3A, esterify each of the 3-hydroxy-17a-ethinyl-5-androstenes prepared in Example by means of p-toluenesulfonyl chloride in pyridine. Isolate the resultant respective products in the described manner to give 9.x-fluoro-17a-ethiny1-5-androstene-38,1'18,178-trio1 3-p-toluenesulfonate,

16a-methyl-17a-ethinyl-5-androstene-38,1 18,178-tri0l 3- ip-toluenesulfonate,

l68-methyl-17u-ethinyl-5-androstene-3 8,1 18,178-triol 3- p-toluenesulfonate,

9a-iluoro-16m-methyl-17u-ethinyl-5-androstene-38,118,

178-triol 3-p-toluenesulfonate,

9ot-fluoro-16ot-ethyl-l7a-ethinyl-S-androstene-3,8,1 18,178-

triol 3-p-toluenesulfonate, r V

, give 9a-fluoro-165-ethyl-17a-ethinyl-S-androstene-35,1 15, 175- triol S-p-toluenesulfonate, 16u-methyl- 1 7a-propinyl-5 -androstene-3 5,1 15,175-triol 3- p-toluenesulfonate, l65-methyl-17u-propinyl=5-androstene-35,1 15,175-tr-io1 3- p-toluenesulfonate, and 9m-flu0ro-16u-methyl-17a-propinyl-5-androstene-35, 1 l 5,

175-triol 3-p-toluenesulfonate, respectively.

E. 17a-ETHINYL-8,5a-CYCLOANDROSTANE- GBJIBJ'YBJIRIOLS In a manner similar to that described in Example 33, treat each of the 17a-ethinyl-5-androstene-35,115,175-triol 3-p-toluenesulfonate esters prepared in Example 16D with aqueous acetone containing potassium acetate. Isolate and purify the resultant respective products in the described manner to give, respectively,

9a-fluoro-l 7a-ethinyl-3 ,Su-cycloandrostan-175-ol-6,11-

dione,

I 16ot -methyl-17tx-ethinyl-3,5 ot-cycloandrostan-175-oi-6,1 1-

dione, 165-1nethyl-17u-ethinyl-3,5a-cycloandrostan-175-01-6, 1 1- dione,

175-01-6, 1:1 -dione, 9a-tluoro-l6wethyl-17a-ethinyl-3 ,5 u-cycloandrostan 175-ol-6,11-dione, 9a-fiUO1O-1 6 5-ethyl- 1 7C-Bth ll'1yl-3,S a-cycloandrostan- 175-ol-6,11-dione, 16a-methyl-l7a-propinyl-3,5ot-cycloandrostan- 175-01- 6,11-dine, 165-methyl-17a-propinyl-3,Sot-cycloandrostan-175-01- 6,11-di0ne, and: 9a-fluoro-1Goa-methyl-17a-propinyl-3,5a-cycloandrostan- 175-ol-6,11-dione, respectively.

EXAMPLE 17 l 7a-ethinyl-4-androsten-1 75-01-6 ,1 1 -di0nes In a manner similar to that described in Example 1, irradiate a dioxan solution of each of 9a-tiuoro-17a-ethinyl-3,5a-cycloandrostan-175-ol-6,11-

l6 ii ri e thyl- 17a-ethinyl-3, a-cycloandrostan-175-01-6, 1 1- 16;:i e thyl-1 7a-ethinyl-3 ,5e-cycloandrostan-175-ol-6,11-

902 53 3214 6x-methyl-17oz-ethinyl-3 ,5 u-cycloan drostan- 175-o1-6,11-dione,

l 4 9a-fiuoro-16 x-ethyl-17a-ethinyl-3,5u-cycloandrostan 175-01-6, 1 l-dione, 9OL-flLIOIO-16/3-6llhy1-170t-Bthll'lY1-3,SOt-CYClOfiHdIOStfiIl- 17 5-ol-6,1 l-dione, 16a-methyl-17a-propinyl-3,5 a-eyclo androstan-l75-ol- 6,1 l-dione, -methyl-17ot-propinyl-3,5 ot-eycloandrostan--ol- 6,1 l-dione, and 9u-fluoro-16a-methyl-17u-propinyl-3 ,5 a-cycloandrostan- 175-01-6, 1 1 -dione using a Hanovia 250 Watt mercury lamp. Isolate and purify the resultant respective products in the manner described to give 9 ot-fiu oro- 17 a-ethinyl-4-androsten-175-01-6, 1 l-dione, 16ot-methyl-17u-ethinyl-4-androsten-175-01-6,1l-dione, 165-methyl-17ot-ethinyl-4-androsten-175-ol-6,1 l-dione, 9oc-flu oro- 1 fia-methyl- 17a-ethinyl-4-androsten-175-01- 6,1 l-dione, 9a-fluoro-16tx-ethyl-l7a-ethinyl-4-androsten-175-ol-6,1 l-

L'dione, 9 a-fiu oro-165-ethyl-l7a-ethinyl-4-androsten-l 7 5- ol-6, 1 1- dione, la-met'hyl-17a-propinyl-4-androsten-175-01-6, 1 l-dione, 165-n1ethyl-17c propinyl-4-androsten-175-01-6,1l-dione,

and 9a-fluoro-l6a-methyl-17a-propinyl-4-androsten-175- ol-6,11-dione, respectively.

EXAMPLE 18 4-pregnen-21-0l-6,20-di0ne In a manner similar to that described in Example 15A,

treat 5-pregnene-35,21-diol-20-one Zl-acetate with ethylene glycol and p-toluenesulfonie acid and isolate the resultant product in the described manner to obtain ZO-ethylenedioxy-5-pregnene-3 5,21-diol ZI-acetate.

In a manner similar to that described in Example 3A, treat 20-ethylenedioxy-5-pregnene-35,2l diol 21 acetate with p-toluenesulfonyl chloride in pyridine and isolate the resultant product in the described manner to obtain ZO-ethylenedioxy-S-pregnene-35-2l-diol 3-p-toluenesulfonate ZI-acetate.

In a manner simflar to that described in Example 3B, treat ZO-ethylenedioxy-5-pregnene-35,21-diol 3-p-toluene sulfonate 21-acetate with potassium acetate in aqueous acetone. Isolate and purify the resultant product in the described manner to obtain 20-ethylenedioxy-3Jot-cyclopregnane-65,21-diol 21-acetate.

In a manner similar to that described in Example 3C, oxidize 20-ethylenedioxy-3,Sa-cyclopregnane 65,21 diol 21-acetate With chromic acid in sulfuric acid. Isolate and purify the resultant product in the described manner to obtain 20-ethylenedioxy-3,Sa-cyclopregnan-Zl-ol 6 one 21acetate.

In a manner similar to that described in Example 1, irradiate a dioxan solution of 20-ethylenedioxy-3,5a-cyclopregnan-Zl-ol-G-one 21-acetate with a 250 Watt mercury arc lamp. Isolate and purify the resultant product in the described manner to obtain 20-ethyleneclioxy-4- pregnen-21-ol-6-one ZI-acetate.

In'a manner similar to that described in Example 15F, reflux a solution of 20-ethylenedioxy-4-pregnen-21-ol-6- one ill-acetate in 60% aqueous acetic acid and isolate and purify the resultant product in a manner similar to that described to obtain 4-pregnen-2l-ol-6,20-dione.

EXAMPLE {19 4-pregene-16u,17a-di0l-6,20-dione p-toluenesulfonic acid to obtain l6u,l7a-isopropylidenedioxy-20ethylenedioxy-S-pregnen-35-ol. Treat the 20- ethylenedioxy ketal derivative with p-toluenesulfonyl chlo- I i.e., 3,8-01 3 p-to1uenesulfonate, is reacted with potassium ace tate in acetone to obtain 16a-benzyloxy-20cthylenedioxy- V and filter.

ride in pyridine and isolate the resultant product to obtain 1606,17OL-lSOPIOPYIlClCIIedlOXY-ZO ethylenedioxy 5 pregnen-BB-ol S-p-toluenesulfonate, which upon treatment with potassium acetate in acetone is converted to 160:,l7aisopropylidencdioxy ethylenedioxy 3,5a cyclopregnan-Gfl-ol which, in turn, is oxidized in chromic acid in sulfuric acid to obtain 160c,l7a-isopropylidenedioxy-20 ethylenedioxy-3,5a-cyclopregnan-6-one. Irradiation of the aforementioned 3,5u-cyclopregnan-6-one derivative in dioxan with a 250 watt mercury arc lamp in the manner of Example 1 yields 16a,17a-isopropylidenedioxy-ZO- ethylenedioxy-4-pregnan-6one.

B. 4 PREGNANE1617a-DIOL-6,20-DIONE Dissolve 1 g. of 16a,17m -isopropylidenedioxy 20- ethylenedioxy 4 pregnan-6-one in refluxing 60% formic acid. Heat under reflux for minutes; then cool the mixture and dilute with water. Filter ofi the resultant precipitate, wash with water, and dry in vacuo. Chromatogr'aphthe solid over Florisil, eluting with ether. Combine the ether eluates and evaporate in vacuo to a residue substantially of 4-pregn-en-e-16u, 17a-diol-6,20- dione. 7

' EXAMPLE 2O 4-pregnen-l 6 oc-Ol-6 ,20-a'i0ne A. 16a-BENZYLOXY-20ETHYLENEDIOXY-3,5a-

CYCLOPREGNAN-G-ONE In a manner similar to that described in Example 158 through ;1=5-D,. l6a benzyloxy-20-ethylenedioxy-S- pregnen-3B-ol is reacted with p-toluenesulfonyl chloride in pyridine and the resultant 3-p-toluenesulf-onate ester,

16a benzyloxy 2'0 ethylenedioxy 5 pregnen- '3,5a-cyclopregnan-6/3-ol. Oxidize the 6B-hydnoxy function with .chromic acid in sulfuric acid to obtain 16ozbenzyloxyQO-ethylenedioxy-3,5u-cycIo-pregnan-6-one.

B. 20-ETHYLENEDIOXY-3,5a-CYCLO-PREGNAN- 16a-OL-6-ONE To 1 g. of 16a benzyloxy 20 ethylene-dioxy-3,5acyclopregnan-6 one in 40 ml. of ethanol add 8 g. of Raney nickel. Reflux the mixture for 8 hours; then cool Evaporat-e the filtrate in vacuo to a residue of 20-ethylenedioxy 3,5oz-cyclopregnan 16u-ol-6-one.

CV. 20-ETHYLENEDIOXY-4-PREGNEN-1Ga-OL-G-ONE In a manner similar to that described in Example 1, irradiate a dioxan solution of 2,0-ethylenedioxy-3,5a cyclopr-egnan-16wol-6-one with a 250 watt mercury arc lamp. Isolate and purify the resultant product in a manner similar to that described to obtain ZO-ethylenedioxy- 4-pregnen-l'6a-ol-6-one.

D. 4-PREGNEN-16a-OL-6,20DIONE In a manner similar to that described in Example 155, treat '20 ethylenedi-oxy 4 pregnen 1 6 ol 6 one in 60% aqueous acetic acid and isolate the resultant product in the described manner to obtain 4-pregnen-l6 ol-6,20-dione.

I claim: 1. A compound selected from the group consisting of 6-k-eto-A -steroids of the following fiormul-a:

15 from the group consisting of hydrogen and methyl; X is .a member selected from the gnoup consisting of hydrogen and halogen; Y is a member selected from the group consisting of keto, (H, ,BOH) [and hydrogen; and when Y is hydrogen, X is hydrogen; and Z is a member selected from the group consisting of I W being a member selected from the group consisting of hydrogen and lower :alk-anoyl; D being a member selected from .the group consisting of hydrogen, lower alkyl, ethinyl, methylethinyl, and ha'logenoethinyl; R being a member select-ed from the group consisting of hydrogen, hydroxy, an acyloxy residue of an acid se- =lected from the group consisting of sulfuric acid, phosphoric acid, and a hydrocarbon carb oxylic acid having up to- 12 carbon atoms; V being a rrrerrrber selected from the group consisting of hydroxy, lower'allcan-oyloxy, and, when R is a member of the group consisting of hydroxy and :an acyl'oxy residue of an acid of the group which comprises irradiating with ultraviolet light a 6 keto-3,5u-cyclo-cyclopentanophenant-hrene having from 18 to 21 nuclear carbon atoms, said 6- keto-3,5a-cyclo-cyclopentanophenanthrene having all reactive 'ketones' other than at 06 protected by a ketone derivative.

13. In the process for preparing a 6-keto-A -cyclopentanophenanthrene of the following structural formula:

wherein A is a member selected from the group consisting of hydrogen, methylene, (H, (x-lower alkyl), (H fi-lower alkyl) and '(H, aOH); R is a member selectedfrom the group consisting of hydrogen and methyl; X is a member selected from the group consisting of hydrogen and halogen; Y is a member-selected from the group consisting of keto, (H, fiOH), and hydrogen, and when Y is hydrogen, X is hydrogen; and Z is a member selected from the group consisting of o ow cum 7 (J- l), and 0 r D being a member selected from the group consisting of hydrogen, lower alkyl, ethinyl, methylethinyl, and halogenoethinyl; W being a member selected from the group consisting of hydrogen, and lower alkanoyl; V being a. member selected from the group consisting of hydrogen, hydroxy, and lower alkanoyloxy; and R is a member selected from the group consisting of hydrogen, hydroxy, and an acyloxy residue of an acid selected from the group consisting of a hydrocarbon carboxylic acid having up to 12 carbon atoms, sulfuric acid and phosphoric acid; and when V is hydroxy, and A is (H, aOI-I), the 160:,17aalkylidenedioxy derivaties thereof; the step which comprises irradiating with ultraviolet light a 6-keto-3,5ot-cyclosteroid of the following formula:

wherein A, R, X, Y, and Z are as defined hereinabove, said 3,5a-cyclo-steroid having all reactive ketones other than at C6 protected by a ketone derivative and said 3,5oc-CyC10-St6IO1d being dissolved in a non-reactive solvent.

14. The process for preparing 17a-ethinyl-19-nor-4- androsten-17f3-ol-6-one 17-acetate which comprises irradiating with ultraviolet light a dioxan solution of 17w ethinyl-19-nor-3-,5u-cycloandrostan-17fi-ol-6-oue 17 acetate.

15. A compound selected from the group consisting of 19-nor-3,5a-cycloandrostanes of the following structural formula:

wherein A is a member selected from the group consisting of hydrogen, methylene, (H, oc-l-OWCI alkyl), (H, fi-lower alkyl), and (H, aOH); K is a member selected from the group consisting of (H, 60H) and keto; D is a member wherein A is a member selected from the group consisting of hydrogen, methylene, and (H, aOH); R is a member selected from the group consisting of hydrogen and methyl; X is a member selected from the group consisting of hydrogen and halogen; Y is a member selected from the group consisting of keto, (H, ,BOH) and hydrogen; and when Y is hydrogen, X is hydrogen; K is a member selected rom the group consisting of keto and (H, 50H); R is a member selected from the group consisting of hydroxy and an acyloxy residue of an acid selected from the group consisting of sulfuric acid, phosphoric acid, and a hydrocarbon carboxylic acid having up to 12 carbon atoms; and V is a member selected from the group consisting of hydroxy, lower alkanoyloxy and hydrogen; and when V is hydroxy and A is (H, aOH), the 16u,17a-alkylidencdioxy derivatives thereof.

References Cited by the Examiner UNITED STATES PATENTS 2,446,538 8/48 Julian et a1. 260-397.5 2,927,119 3/60 Ellis et a1. 260-3975 3,002,969 10/61 Petrow et al. 260239.55 3,071,581 1/ 63 Zderic et a1 260239.55 3,094,523 6/63 Sletzinger et a1. 260239,55

OTHER REFERENCES Werder: Chem. Berichte 95, pp. 773-776 (1962).

LEWIS GOTTS, Primary Examiner. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 6-KETO-$4-STEROIDS OF THE FOLLOWING FORMULA: 